In response to NCI PQ9, we propose to generate platelet-sparing BCL-XL Proteolysis Targeting Chimeras (PROTACs) or BCL-XL-Ps for the treatment of cancer, particularly pancreatic cancer (PC), because BCL-XL is one of the most important and best validated cancer targets and has been identified as the most important drug resistance gene in human PC cells. Potent BCL-XL selective inhibitors and BCL-XL and BCL-2 dual inhibitors such as ABT263 (or navitoclax) have been developed. However, the on-target and dose-limiting thrombocytopenia of these inhibitors has hampered their clinical translation because platelets solely depend on BCL-XL for survival. We hypothesize that we can circumvent BCL-XL inhibition-induced platelet toxicity by converting ABT-263 into BCL-XL-Ps that target BCL-XL to an E3 ligase poorly expressed in platelets for ubiquitination and degradation, because BCL-XL-Ps depend on the E3 ligase to promote BCL-XL ubiquitination and degradation by the ubiquitin proteasome system (UPS). This hypothesis is supported by our preliminary data demonstrating that our newly generated BCL-XL-Ps, which target BCL-XL to the cereblon (CRBN) or von Hippel-Lindau (VHL) E3 ligase, are capable of degrading BCL-XL in various cancer cells examined but have minimal effects on the BCL-XL levels in human platelets, because platelets express significantly lower levels of CRBN and VHL than these cancer cells. As such, these BCL-XL-Ps are more potent against BCL-XL dependent human cancer cell lines but significantly less toxic to platelets than ABT263 in vitro. Compared with ABT-263, one of our lead BCL-XL-Ps exhibited improved antitumor activities in a number of xenograft mouse models without causing thrombocytopenia. In addition, we found that the BCL-XL-Ps converted from ABT263 can specifically degrade BCL-XL but not BCL-2, indicating that the conversion increased the specificity of ABT263. It is well established that inhibition of BCL-XL can sensitize tumor cells to chemotherapy, whereas BCL-2 inhibition exacerbates chemotherapy-induced neutropenia by suppressing granulopoiesis. Thus, this increased specificity of BCL-XL-Ps can potentially reduce another on-target toxicity of ABT263, i.e. neutropenia, which is dose-limiting and prevents the combination of ABT263 with a standard-of-care cytotoxic chemotherapeutic agent to treat cancer. Furthermore, our BCL-XL-Ps are also potent senolytic agents that can selectively kill senescent cells (SnCs) induced by chemotherapy and radiation, because SnCs also rely on BCL-XL for survival. Clearance of chemotherapy-induced SnCs has the potential to improve the therapeutic efficacy of standard-of-care chemotherapy, because SnCs play an important role in mediating the induction of many adverse effects of chemotherapeutic drugs as well as promoting cancer chemoresistance, relapse and metastasis, in part via expression of the senescence-associated secretory phenotype (SASP). Collectively, these findings suggest that BCL-XL-Ps are superior to conventional BCL-2/BCL-XL dual inhibitors and BCL-XL selective inhibitors as novel antitumor and senolytic agents. Based on these promising preliminary data, we plan to pursue the following specific aims: 1) Design and synthesize new BCL-XL-Ps with improved antitumor and senolytic activities but reduced on-target toxicities; 2) Evaluate the antitumor and senolytic activities and on- and off-target toxicities of lead BCL-XL-Ps in vivo; 3) Determine whether lead BCL-XL-Ps can improve the therapeutic efficacy of gemcitabine for PC. Development of platelet-sparing BCL-XL-Ps has the potential to transform the treatment of BCL-XL-dependent solid tumors and hematological malignancies and dramatically improve the treatment of solid tumors such as PC by chemotherapy.